Search results

There are several proteolytic fragments or specific domains of proteins that act as inhibitors of angiogenesis. These include fragments of plasminogen such as Angiostatin protein kringles 1-4 and kringles 1-5, Endostatin, Restin, PEX, the N-terminal fragment of prolactin, and the Nterminally truncated platelet factor. Angiostatin is a proteolytic protein fragment of plasminogen that is comprised of the first 4 kringle regions. Angiostatin k1-4 prevents the growth of endothelial cells, and its systemic administration inhibits the growth of primary carcinomas in mice. Angiostatin Kringles 1-3 segment has a larger inhibitory activity than the Angiostatin kringles 1-4 fragment. The protease-activated angiostatin kringles 1-5 is the most potent plasminogen fragment with over 50 times larger endothelial cell specific inhibitory activity. Angiostatin kringles 1-5 systemic administration inhibits growth of fibrosarcoma and significantly reduces neovascularization.
Angiostatin is an angiogenesis inhibitor in mouse serum and urine. Angiostatin is a 38 kDa protein fragment of the plasminogen composed of the 1st 4 kringle domains of plasminogen. Angiostatin K1-4 is also named plasminogen kringles 1-4 and PK1-4.
Angiostatin protein is manufactured by the protelytic cleavage of plasminogen by a serine protease from several prostate carcinoma cell lines. The manufacturing of angiostatin by pancreatic cancer cells can be inhibited by TGF-beta 1 along with plasminogen activator inhibitor type-1 (PAI1).

ACTN1 encodes a nonmuscle, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments.

Leptin takes an important part in the regulation of energy balance and body weight control.After entering the circulation, Leptin binds LEPRwhich results in the activation of several major signalling pathways. In the hypothalamus Leptin acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption and also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, regulates pancreatic beta-cell function and insulin secretion and affects innate and adaptive immunity.

SELPLG glycoprotein functions as a high affinity counter-receptor for the cell adhesion selectin molecules (P, E and L) located in stimulated T lymphocytes and myeloid cells. SELPLG binds leukocytes to activated platelets or endothelia expressing selectins, a vital role in leukocyte trafficking throughout inflammation. In order to have a high-affinity binding activity SELPLG needs two post-translational modifications, tyrosine sulfation and the addition of the sialyl Lewis x tetrasaccharide (sLex) to its O-linked glycans. Polymorphisms and abnormal expression of SELPLG are linked to defects in the innate and adaptive immune response. Alternate splicing results in multiple transcript variants.

Follistatin is a single-chain gonadal protein that specifically inhibits follicle-stimulating hormone release. The single FST gene encodes two isoforms, FST317 and FST344 containing 317 and 344 amino acids respectively, resulting from alternative splicing of the precursor mRNA. In a study in which 37 candidate genes were tested for linkage and association with polycystic ovary syndrome (PCOS) or hyperandrogenemia in 150 families, evidence was found for linkage between PCOS and follistatin. Follistatin binds directly to activin and functions as an activin antagonist. specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone (fsh).

SKP1 is a F-box enzyme which functions as a substrate recognition component of the SCF ubiquitin ligase complex which controls the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SKP1 binds to proteins containing an F-box motif, such as cyclin F, S-phase kinase-associated protein 2, and other regulatory proteins involved in ubiquitin dependent proteolysis. SKP1 takes part in the control of beta-catenin levels and the activity of beta-catenin dependent TCF transcription factors. SKP1 serves as an adapter that links the F-box protein to CUL1 in the SCF complex.

Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. This gene encodes a growth regulator which inhibits the proliferation of a number of tumor cell lines. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells.

Kallikrein-3 (KLK3) is a part of the kallikrein-related peptidase family. Kallikreins are a subgroup of serine proteases having various physiological functions. Numerous kallikreins take part in carcinogenesis and some may be prospective cancer and other disease biomarkers. Kallikrein-3 is 1 of the 15 kallikrein subfamily members located in a cluster on chromosome 19 and is a protease present in seminal plasma. KLK3 hydrolyzes semenogelin-1 consequently leading to the liquefaction of the seminal coagulum. KLK3 acts normally in the liquefaction of seminal coagulum, probably by hydrolysis of the high molecular mass seminal vesicle protein. Serum level of the KLK3 protein, called PSA in the clinical setting, is beneficial in the diagnosis and monitoring of prostatic carcinoma.

Platelet factor-4 is a 70-amino acid protein that is released from the alpha-granules of activated platelets. Its major physiologic role appears to be neutralization of molecules on the endothelial surface of blood vessels, thereby inhibiting local antithrombin III activity and promoting coagulation. As a strong chemoattractant for neutrophils and fibroblasts, PF4 probably has a role in inflammation and wound repair. Oncostatin-A is a member of the CXC chemokine family. Furthermore it is used as an inhibitor in the angiogenesis during tumor therapy.

Eledoisin is an undecapeptide formed in the venom gland of several species of octopuses and is used as a vasodilator and a contraction agent of extravascular smooth muscle.

Kallikreins are a subgroup of serine proteases having various physiological functions. Many kallikreins are implicated in carcinogenesis and some have potential of becoming novel cancer and other disease biomarkers. Kallikrein-13 (KLK13) is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. KLK13 gene expression is regulated by steroid hormones and may be useful as a marker for breast cancer.

Osteoprotegerin, which is a member of the tumor necrosis factor receptor superfamily and is involved in the regulation of bone metabolism. OPGand its ligand (OPGL) are cytokines regulating osteoclasto-genesis. OPGL binds to receptors on the surface of preosteoclasts and stimulates their differentiation into active osteoclasts. This leads to osteoresorption. OPG inhibits this osteoclasto-genesis (OPG is secreted by osteoblasts, and binds to OPGL, thus inhibiting maturation of osteoclasts and osteoresorption). The degree and activity of osteoresorption depend mainly on the balance between OPG and its ligand (OPGL); factors increasing OPGL expression mostly reduce OPG expression and vice versa.

Cleavage stimulation factor subunit 1 (CSTF1) is involved in the polyadenylation and 3'end cleavage of pre-mRNAs. The CSTF1 gene encodes one of three subunits which merge to produce cleavage stimulation factor (CSTF). Like the mammalian G protein beta subunits, CSTF1 contains transducin-like repeats. CSTF1 is one of the numerous factors necessary for polyadenylation and 3'-end cleavage of mammalian pre-mRNAs. CSTF1 is responsible for the interaction of CSTF with other factors to create a stable complex on the pre-mRNA.

Collagen, a major component of the extracellular matrix, is a fibrous protein that provides tensile strength to tissues giving them structural integrity. Collagen and its derivative, gelatin, have been widely used in medical, pharmaceutical and consumer products for more than 100 years. The supply of these materials, created from animal remains, is both abundant and inexpensive. However, most formulations are not highly purified and have the potential to cause an inflammatory reaction in some product users. In addition, concerns have been raised over the last several years about the potential for contamination of bovine products with the agent that causes mad cow disease and its human variant, Creutzfeldt-Jakob Disease. Animal collagens are subject to extensive modifications that continue over the life of the molecule in the extracellular space. These differences influence both the extractability of collagens from tissue and the biophysical characteristics of these collagens. As a result, collagens isolated from tissues exhibit significant lot-to-lot variability and, as bulk materials, are often analytically intractable. Products that contain animal-derived collagen can induce potentially harmful inflammatory or immune responses in humans and pose risk of contamination with viruses or prions, potentially life-threatening pathogens. Recombinant collagens are essentially identical to the native collagen protein thereby reducing the risk of inflammation, immune response, and disease as compared to animal-sourced collagen.

The mammaglobin gene was first identified using a differential screening approach directed at the isolation of novel, human breast cancer-associated genes. Mammaglobin encodes a 10 kDa glycoprotein and is distantly relaetd to a family of epithelial secretory proteins that includes rat estramustine-binding protein/prostatein and human Clara cell 10 kDa protein (CC10)/uteroglobin. Mammaglobin, a mammary-specific member of the uterglobin family, is known to be overexpressed in human breast cancer. Studies suggest that mammaglobin is one of the first relatively mammary-specific and mammary-sensitive markers (85%). Mammaglobin may be valuable used in a panel with BRST-2 (GCDFP-15) and ER in evaluating tumors of unknown primary sites.
SCGB2A2 (the mammaglobin gene) is located on chromosome 11, at locus 11q13. SCGB2A2 is member of the secretoglobin superfamily of which is a group of small dimeric secreted and sometimes glycosylated proteins. Expressed mainly in mucosa, secretoglobins appear to be involved in cell signalling, immune response, chemotaxis, and might also serve as transporters for steroid hormones in humans.

Procollagen C-endopeptidase enhancer 1, also known as PCOLCE binds to the C-terminal propeptide of type I procollagen and enhances procollagen C-proteinase activity. In addition, C-terminal processed part of PCPE (CT-PCPE) has a metalloproteinase inhibitory activity. Among the diseases which are associated with PCOLCE: bone fracture & oculopharyngeal muscular dystrophy.

Kallikrein-10 (KLK10) is one of the 15 kallikrein subfamily members located in a cluster on chromosome 19. Kallikreins are a subgroup of serine proteases having various physiological functions. KLK10 is secreted and has a role in suppression of tumorigenesis in breast and prostate cancers.

Plasma fibronectin level is elevated in severe coronary artery disease. Increased plasma fibronectin levels are related with venous thromboembolism (VTE) particularly in males, and extend the probable association between biomarkers and risk factors for arterial atherothrombosis and VTE. Fibronectin plays a role in several cellular processes, including tissue repair, embryogenesis, blood clotting, and cell migration/adhesion. Fibronectin consists in two main forms: 1) as an insoluble glycoprotein dimer that serves as a linker in the extracellular matrix and 2) as a soluble disulphide linked dimer found in the plasma. The plasma form is produced by hepatocytes, and the ECM form is synthesized by fibroblasts, chondrocytes, endothelial cells, macrophages, as well as certain epithelial cells. Fibronectin also takes part as a general cell adhesion molecule by anchoring cells to collagen or proteoglycan substrates. Fibronectin organizes cellular interaction with the ECM by binding to different components of the extracellular matrix and to membrane-bound Fibronectin receptors on cell surfaces.

Stem cell factor / KIT ligand (SCF) is a cytokine which binds CD117(c-Kit). SCF is also known as "steel factor" or "c-kit ligand". SCF exists in two forms, cell surface bound SCF and soluble (or free) SCF. Soluble SCF is produced by the cleavage of surface bound SCF by metalloproteases.
SCF is a growth factor important for the survival, proliferation, and differentiation of hematopoietic stem cells and other hematopoietic progenitor cells. One of its roles is to change the BFU-E (burst-forming unit-erythroid) cells, which are the earliest erythrocyte precursors in the erythrocytic series, into the CFU-E (colony-forming unit-erythroid).

Platelet factor-4 is a 70-amino acid protein that is released from the alpha-granules of activated platelets and binds with high affinity to heparin. Its major physiologic role appears to be neutralization of heparin-like molecules on the endothelial surface of blood vessels, thereby inhibiting local antithrombin III activity and promoting coagulation. As a strong chemoattractant for neutrophils and fibroblasts, PF4 probably has a role in inflammation and wound repair. Oncostatin-A is a member of the CXC chemokine family. Human PF4 is used for the proof of heparin-induced thrombocytopenia. Furthermore it is used as an inhibitor in the angiogenesis during tumor therapy.

CALR is a multifunctional protein that acts as a main Ca(2+)-binding (storage) protein in the lumen of the endoplasmic reticulum. Calreticulin is localized in the nucleus, and participates in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is nearly identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. CALR binds to antibodies in specific sera of systemic lupus and Sjogren patients which have anti-Ro/SSA antibodies, it is well conserved among species, and it is positioned in the endoplasmic and sarcoplasmic reticulum where it binds calcium. The amino terminus of CALR interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. CALR reduces the binding of androgen receptor to its hormone-responsive DNA element and inhibits androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Therefore, CALR acts as a significant modulator of the regulation of gene transcription by nuclear hormone receptors.

TRIM21 is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The 52 kDa Ro protein is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus. Ro/SSA interacts with autoantigens in patients with Sjogren syndrome and systemic lupus erythematosus. Ribonucleoprotein particle is composed of a single polypeptide and one of four small RNA molecules. The RoSSA is present in all mammalian cells studied but has no known function. At least 2 isoforms are present in nucleated and red blood cells, and tissue specific differences in Ro/SSA proteins were identified.

Osteoprotegerin acts as decoy receptor for rankl and thereby neutralizes its function in osteoclastogenesis. OPG inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local rankl/opg ratio. Osteoprotegerin may also play a role in preventing arterial calcification. May act as decoy receptor for trail and protect against apoptosis. Trail binding blocks the inhibition of osteoclastogenesis.

Killer Cell Lectin-Like Receptor Subfamily C, Member 1 (KLRC1) is a part of the killer cell lectin-like receptor family. KLRC1 functions as a receptor for the detection of MHC class I HLA-E molecules by NK cells and some cytotoxic T-cells. KLRC1 is also connects with CD94 and is expressed on NK cells and some activated T cell.